Infiammazione. Proteine di fase acuta negative: albumina; transferrina.

Transcription

1 Infiammazione Proteine di fase acuta positive: a1 antitripsina, amiloide serica, aptoglobina, a1 antichimotripsina, a2-macroglobuline, ceruloplasmina, PCR, fibrinogeno, b-lipoproteine, pro-calcitonina. Proteine di fase acuta negative: albumina; transferrina. Proteine di fase cronica: IgG, C3

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4 IMMUNOPATOLOGIA: MEMENTO

5 Reazioni da ipersensibilità

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10 Anemie emolitiche autoimmuni (Ipers. II tipo) 10

11 Morbo di Graves 11

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13 DAMP/PAMP 13

14 Functional development and activity of Th cell subpopulations

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16 Extrinsic inflammasomopathies: Familial Mediterranean Fever (FMF) Pyogenic Arthritis grangenous Pyoderma and Acne (PAPA) Synovitis Acne Pustolosis Hyperostosis Osteitis (SAPHO) Intrinsic inflammasomopathies: Familial Cold Autoinflammatory Syndrome (FCAS) Muckle-Wells Syndrome (MWS) Chronic Infantile Neurological Cutaneous and Articular syndrome (CINCA) (Neonatal Onset Multisystemic Inflammatory disease, NOMID)

17 Any relevance to human diseases? Autoinflammatory diseases pyrin Familial Mediterranean Fever (FMF) CIAS1-associated periodic syndrome(s) (cryopyrinopathies) cryopyrin Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome Chronic infantile neurological cutaneous and articular syndrome (CINCA)

18 Immunodeficiency Definition: When the immune system is depressed or absent and an individual is unable to mount a normal immune response to satisfactorily protect the body.

19 Types of Immunodeficiency Primary immunodeficiency: Inherited or congenital. Part of the immune system is missing or does not function properly. Caused by defects in immune cell development or mutation in particular molecules. Severe form:present in early life. Less severe forms:may not cause problems until later in life. Secondary immunodeficiency: previously functional immune system compromised by factors outside the immune system, such as viruses, aging, radiation, malnutrition, severe stress, splenectomy, thymectomy or chemotherapy. More common than primary immunodeficiency.

20 SCID: severe combined immunodeficiency disease lose of the humoral immunity and cellular immunity at the same time 1. Autosomal recessive SCID a) Immunological features:defect of the common precursors of T and B cells Defects in IgG and TCR gene rearrangenent (RAG-1 and RAG-2) ADA gene mutations b) Defects in MHC I/MHC II molecule SCID (sindrome del linfocita nudo, tipo I e tipo II) tipo I: deficit di TAP1 o TAP2 (Ag transport across ER membrane) tipo II: deficit fattori di trascrizione geni MHC II Immunological features: increased susceptibility to virus infection, 2. X-linked recessive SCID no CD4 + T cells in peripheral blood decreased function of B cells 2a. Pathogenesis:gene mutation of IL-2, IL-4, IL-7, IL-9, IL-15 common receptor g chain. Defects in Jak3. Reduced numbers of peripheral blood T cells and NK cells. 2b. Wiskott-Aldrich (WAS) (WASp is 502 aa-long protein mediating signal transduction to the cytoskeleton) Platelets and lymphocytes. Wiskott-Aldrich protein (cytoskeleton) (trombocitopenia, eczema, infezioni ricorrenti)

21 Adenosine-Deaminase (ADA) Deficiency ADA is responsible gene in ~20% SCID. ADA ADA is is responsible gene gene in ~20% in ~20% SCID. SCID. Often fatal, if untreated, due to infections. Often fatal, if untreated, due to infections. Often fatal, if untreated, due to infections. It was the first form of SCID where: It was the first form of SCID where: It was 1. genetic the first form cause of was SCID identified where: (1972), 1. genetic 1. genetic cause cause was was identified (1972), 2. responsible gene was cloned (1983), responsible gene gene was was cloned (1983), 3. gene 3. gene therapy therapy was was approached (1990), 3. gene therapy was approached (1990), 4. effective 4. effective treatment treatment (PEG-ADA) other other 4. effective than HSCT treatment was developed (PEG-ADA) (1990). other than HSCT was developed (1990). than HSCT was developed (1990). PEG-ADA enzyme replacement therapy: 1. FDA approved orphan drug (1990), PEG-ADA enzyme replacement therapy: PEG-ADA 2. Bi-weekly enzyme I.M., replacement therapy: 1. FDA 3. approved Can restore, orphan sustain drug immunity, (1990), 1. FDA approved orphan drug (1990), 2. Bi-weekly 4. Expensive I.M., ($ ,000/yr). 2. Bi-weekly I.M., 3. Can restore, sustain immunity, 3. Can restore, sustain immunity, 4. Expensive ($ ,000/yr). 4. Expensive ($ ,000/yr).

22 Metabolismo dell ATP e del datp

23 Patologia cellulare del deficit di ADA Adenosine

24 Terapia

25 FCAS: sindrome autoinfiammatoria familiare da freddo; MWS, sindrome di Muckle-Wells; NOMID, sindrome neonatale infiammatoria multisistemica; FMF, febbre familiare mediterranea; PAPA, artrite piogenica, pioderma gangrenosa ed acne

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28 Protein misfolding disorders Healthy brain Alzheimer brain

29 Basics of Inflammation

30 Each cell commits to recruit and activate others based on multiple imputs, generally requiring evidence of both injury and infection Carl Nathan, 2002 Infection: PAMPs Injury: DAMPs

31 E sempre questo il destino del parassita?

32 Stranger versus Danger DAMP PAMP PRR Modified from From Heath and Carbone, Nature 425: , 2003

33 Pathogen Associated Molecular Patterns (PAMPs) what are they? Broadly diffuse determinants that are usually absent from mammalian cells but commonly expressed by pathogens LipoPolySaccharide Teichoic acid Lipoarabidomannan Double-stranded RNA Bacterial DNA (unmethylated CpG sequences) PAMPs = signals of foreignness Why PAMPs? Because humans are (notoriously) blue while extraterrestrials are (notoriously) green

34 Damage Associated Molecular Patterns (DAMPs) what are they? Molecules restricted to the intracellular environment, usually absent from the extracellular space that signal cell injury or stress. Modified extracellular matrix constituents (?)

35 How are PAMP and DAMP signals integrated? PAMP CPU? P2X7 DAMP

36 The inflammasome

37 What is the inflammasome? IPAF Casp-1 IPAF/NAIP inflammasome PAMP PAMP IPAF Casp-1 NAIP Pyrin pyrin domain ASC Casp-1 NALP3 inflammasome NALP3 PAMP

38 Any relevance to human diseases? Autoinflammatory diseases pyrin Familial Mediterranean Fever (FMF) CIAS1-associated periodic syndrome(s) (cryopyrinopathies) cryopyrin Familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome Chronic infantile neurological cutaneous and articular syndrome (CINCA)

39 L inflammasoma The inflammasome is a molecular multiprotein complex located within the cell cytoplasm of (mainly) immune cells, and responsible for the processing and activation of pro-caspase-1 into caspase-1, and the conversion of pro-il-1b and pro-il-18 Into their respective mature forms

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41 Figura Polarizzazione delle risposte infiammatorie croniche. Dal volume: Pontieri Patologia Generale Piccin Nuova Libraria S.p.A.

42 Interleukin-1b (IL-1b) Activation of cells of innate immunity In vivo IL-1b production Healthy = 6 ng/day CAPS = 31 ng/day From Lachmann et al., JEM 2009 Dinarello, J Exp Med 2005

43 Familial Mediterranean Fever Familial Mediterranean Fever (FMF) is also called recurrent polyserositis. The salient features of this disease include brief recurrent episodes of peritonitis, pleuritis, and arthritis, which are usually associated with fever. The disease occurs within families and is much more common in individuals of Mediterranean descent than in persons of any other ethnicity. Nephrotic syndrome: Before the institution of colchicine therapy, mortality from nephrotic syndrome was almost universal by age 50 years in North African Sephardic Jewish patients. Among other Sephardic Jewish, Ashkenazi Jewish, and Armenian patients, amyloidosis was extremely rare. The mortality rate among Turkish patients was high, but this high rate may have represented selection bias. No pre colchicine-therapy data are available from Arabic patients. Appendectomies: Many undiagnosed FMF patients had appendectomies because the severity of the peritoneal episodes seemed to indicate appendicitis. Chronic arthritis: Approximately 5% of patients may develop chronic arthritis that sometimes leads to destructive arthritis of hips or knees and may necessitate joint replacements. Approximately 10% of patients with chronic arthritis develop seronegative spondyloarthropathy. Fertility and pregnancy: Approximately one third of female patients are infertile, and 20-30% of pregnancies result in fetal loss.

44 Causes: FMF is a recessive genetic disease likely caused by missense and nonsense mutations in the MEFV gene that is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or (marenostrin). Multiple mutations are located on the MEFV gene. Most of the mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation in exon 1 at amino acid 148 may represent as many as one quarter of the known mutations. Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent. Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis. Patients with V726A (alanine for valine at position 726) may be less likely to develop amyloidosis.

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47 The Inflammasome a IL-1b producing machinery Le inflammasomopatie

48 Nucleotide-oligomerization domain NOD1 NOD2 NLRC3 NLRC5 NLRX1 NLR: NOD-like receptors NALPs (NLRPs) IPAF (NLRC4) NAIP CIITA Associated with the inflammasome

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53 Anemie emolitiche autoimmuni (Ipers. II tipo) 53

54 Morbo di Graves 54

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56 Figura Patologie correlate alla deposizione degli immunocomplessi. Dal volume: Pontieri Patologia Generale Piccin Nuova Libraria S.p.A.